Abstract Recent improvements in humanized mice can now provide HIV investigators with small animal models enabling them to study more of the important aspects of HIV infection than previously possible, including mucosal transmission of virus, the generation of anti-HIV immune responses, and the development of viral latency. The Animal and Laboratory Core (Core B) will provide this U19 Program with ?BLT? (bone marrow?liver?thymus) humanized mice, generated by surgically implanting human fetal thymic and liver tissue under the renal capsules of immunodeficient mice, concurrently with the intravenous transfer of autologous human hematopoietic stem cells (HSCs). We and/or others have demonstrated that in these BLT mice: 1) the bone marrow niche is occupied with human HSCs that support human hematopoiesis; 2) latent reservoirs of infection develop following HIV mucosal transmission; and 3) virus-specific cellular immune responses are generated in HIV infection that recapitulate HLA-restricted immunodominance patterns of human infection and have already demonstrated some capacity to constrain HIV replication. These mice will therefore provide Project 1, 2 and 3 investigators with a uniquely suitable small animal model in which to develop and preclinically evaluate a ?Defend and Destroy? approach to a functional cure of HIV infection. By using CRISPER/Cas to re-engineer both autologous HSCs and CD8+ T cells, these investigators propose to develop the ability to defend target cells arising from the edited HSCs against HIV infection, and to destroy latent HIV reservoirs by generating a large, highly activated HIV-specific cellular immune response with edited T cells. Core B will generate BLT mice for all experiments using them that are proposed in Projects 1, 2 and 3 of this U19 Program application. As called for by different experiments, these BLT mice will be generated either with unmanipulated or with genetically manipulated HSCs. Core B will perform all treatments of BLT mice called for, including HIV infection, administration of anti-retroviral therapies (ART), and adoptive transfer of genetically manipulated HSCs or CD8+ T cells. Core B will also acquire all peripheral blood samples from live uninfected and HIV-infected mice, and blood and tissues from mice at the time of sacrifice. A strong safety plan is in place to minimize the risk of HIV exposure to Core personnel performing BLT HIV infections and analyses of HIV-infected BLT mice, and emergency procedures are in place in case any exposure does occur. Finally, Core B will also provide virologic support to Projects 1, 2 and 3, generating and titering the stocks of HIV used to infect BLT mice, and measuring plasma and tissue viral loads in HIV-infected mice by qRT-PCR.